Bone Marrow and Cardiac Progenitor Cells in Cardiac Repair

描述（由申请人提供）：虽然几个实验室已经确定了心脏祖细胞（CPCs），但关于成人心脏中心肌细胞再生的争议尚未解决。同样，骨髓衍生祖细胞（BMPCs）的可塑性及其获得肌细胞谱系和再生死亡心肌的能力也受到挑战。因此，该应用的主要目的之一是通过一种涉及遗传标记和克隆标记的新方法来确定c-kit阳性的BMPCs和cpc是否获得心脏表型并产生大量肌细胞承诺的后代。这两类祖细胞对急性和慢性缺血性心力衰竭的治疗效果取决于它们(a)在受损心脏的敌对环境中存活的能力，(b)在心肌内移植的能力，以及(c)生长和分化的能力。BMPCs可能具有生长潜力，这优于CPCs，但转分化可能会影响这一特性，而CPCs可能是心脏修复的一种更强大的治疗形式。转分化过程可能改变BMPCs的生长行为，通过端粒-端粒酶系统的改变，细胞过早衰老和凋亡，BMPCs可能部分失去分裂能力。同样，来源于BMPCs的肌细胞在获得成人表型方面可能具有固有的局限性。相反的情况也可能是正确的，BMPCs即使在转分化后也可能比cpc保持更强的再生能力，代表最适合受损心脏的细胞。对于BMPCs，新形成的肌细胞似乎具有胎儿-新生儿的特性，可能不会达到成人的表型，这个问题可能不会影响cpc的承诺。1边界的相对缺氧和梗死可能会调节Notch通路，而延长的Notch激活可能会抑制Nkx2.5的下调，从而抑制早期到晚期肌细胞分化的转变。Notch可能抑制GATA4的转录，这可能对不可逆的肌细胞承诺至关重要。这种行为符合分化延迟模型，其中Notch的持续存在反对成熟的进展。最后，提出的工作解决了在缺血性心力衰竭中，BMPCs在心肌细胞和冠状血管再生方面是否优于、等于或不如CPCs的问题。

DESCRIPTION (provided by applicant): Although several laboratories have identified cardiac progenitor cells (CPCs), the controversy concerning myocyte regeneration in the adult heart has not been resolved. Similarly, the plasticity of bone marrow derived progenitor cells (BMPCs) and their ability to acquire the myocyte lineage and regenerate dead myocardium has been challenged. Therefore, one of the major objectives of this application is to determine by a novel approach that involves genetic tagging and clonal marking, whether c-kit-positive BMPCs and CPCs acquire a cardiac phenotype and give rise to a large number of myocyte-committed progeny. The therapeutic efficacy of these two classes of progenitor cells for acute and chronic ischemic heart failure depends on their ability (a) to survive in the hostile milieu of the damaged heart, (b) to engraft within the myocardium, and (c) to grow and differentiate. BMPCs may have a growth potential, which is superior to CPCs but transdifferentiation could affect this characteristic and CPCs may constitute a more powerful form of therapy for cardiac repair. The process of transdifferentiation may alter the growth behavior of BMPCs, which may lose in part their capability of dividing through alterations of the telomere-telomerase system, premature cellular senescence, and apoptosis. Similarly, myocytes derived from BMPCs may possess inherent limitations in the acquisition of the adult phenotype. The opposite may also be true and BMPCs may retain even after transdifferentiation a stronger regenerative capacity than CPCs representing the most appropriate cells for the damaged heart. With BMPCs, the newly formed myocytes appear to have fetal- neonatal properties and may not reach the adult phenotype, a problem that may not affect the commitment of CPCs. Relative hypoxia at the1 border and infarct may modulate the Notch pathway, and prolonged Notch activation may inhibit downregulation of Nkx2.5 and, thereby, the transition from early to late myocyte differentiation. Notch may repress transcription of GATA4, which could be critical for irreversible myocyte commitment. This behavior conforms to a model of differentiation delay in which the persistence of Notch opposes the progression of maturation. Ultimately, the proposed work addresses the question whether BMPCs are superior, equal, or inferior to CPCs for the regeneration of cardiomyocytes and coronary vessels in ischemic heart failure.